Cushing's disease (CD) is the result of excess secretion of adrenocorticotropic hormone (ACTH) by a benign monoclonal pituitary adenoma. The excessive secretion of ACTH stimulates secretion of cortisol by the adrenal glands, resulting in supraphysiological levels of circulating cortisol. The pathophysiological levels of cortisol are associated with hypertension, diabetes, obesity, and early death. Successful resection of the CD-associated ACTH-secreting pituitary adenoma is the treatment of choice and results in immediate biochemical remission with preservation of pituitary function. Accurate and early identification of CD is critical for effective surgical management and optimal prognosis. We recently reviewed the current pathophysiological principles, diagnostic methods, and management of CD. While it is known that up to 20% or so of patients with CD recur after apparently successful transsphenoidal tumor resection, little is known about what factors may predict recurrence. Perioperative increases in adrenocorticotropic hormone (ACTH) and cortisol mimic corticotropin releasing hormone (CRH) stimulation testing. This phenomenon may help identify patients with residual adenoma after transsphenoidal surgery (TSS) for Cushing's disease (CD). We retrospectively evaluated whether early post-operative measurements of ACTH and cortisol would be helpful in this regard. This was a case control study of 291 consecutive patients treated at NIH from December 2003 till July 2016. Early and medium-term remission were assessed at 10 days and 11 months. 257 patients had biochemical evidence of CD. Normalized early post-operative values (NEPV) for cortisol and ACTH were calculated as immediate post-operative cortisol or ACTH minus preoperative post-CRH stimulation test levels. The NEPV for cortisol and ACTH predicted early non-remission (adjusted OR 1.1, 95% CI 1.0 - 1.1, P = 0.016; and adjusted OR 1.0, 95% CI 1.0 - 1.0, P = 0.048 respectively). ROC for NEPV cortisol was 0.78, 95% CI 0.61 - 0.95; and for NEPV ACTH was 0.80, 95% CI 0.61 - 0.98. NEPV for both cortisol and ACTH predicted medium-term non-remission (hazard ratios (HR) 1.1, 95% CI 1.0 - 1.1, P = 0.023; and HR 1.0, 95% CI 1.0 - 1.0, P = 0.025 respectively). Thus, NEPV for cortisol and ACTH may help predict non-remission after TSS for CD.